tbuckley/cabot-search huggingface dataset:
Hemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: A pharmacovigilance study from FDA Database.
Authors: Niraj Neupane, Shreeja Shikhrakar, Sangharsha Thapa, Asis Shrestha
Journal: Journal of Clinical Oncology (2023)

e14684 Background: Immune checkpoint inhibitors (ICIs) are increasingly used to treat multiple cancers uncovering varieties of immune-related adverse events (irAEs). ICI-related haemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome caused by exaggerated activation of macrophages and cytotoxic T cells resulting in fatal hematological toxicity and multi-organ damage. Methods: We conducted a retrospective analysis of reported cases of HLH in patients treated with checkpoint inhibitors using data from the FDA's Adverse Event Reporting System (FAERS) database from 2018 to 2022. Patients aged 18 or older were included, and cases were classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Results: Of 2,317 patients with HLH reported in the FAERS, 13.6% (315) of patients were reported to receive commonly used ICIs. With nivolumab being 44.93%%, pembrolizumab 35.87%, Ipilimumab 30.43%, and atezolizumab 15.94%. HLH among these ICI use was most commonly reported in males (65.2%) with a median age of 65. Melanoma was the most common cancer reported in this sample population. Out of the reported cases, 26% died, and 72% were males. Death was observed more in combination ICI therapy (40.73%) than in single-agent use (29.04%). Even though the most commonly reported HLH was with Nivolumab, mortality was highest with Atezolizumab use (29.55%). Conclusions: Nearly half of the patients with a diagnosis of HLH received commonly used ICIs, which points towards ICIs being one of the important risk factors for developing HLH. However, several confounders should be considered, like a cancer diagnosis, infection, and antibiotics. Further studies on ICI-induced HLH are necessary to establish its causal relationship.
Modulating MDSCs by HF1K16: A mono-therapy phase Ia study examining safety and preliminary efficacy in patients with refractory and metastatic cancer.
Authors: Yuhong Xu, Anjie Zheng, Ruofan Huang, Jian Liu, Xiaochen Zhang, Jian Chen, Hongming Fang, Yongchao Dai, Jianming Liu, Shanshan Jin, Xuan Wu, Xun Wang, Wenjun Guo, Yongfeng Huang, Jinsong Wu
Journal: Journal of Clinical Oncology (2023)

e14040 Background: Immature myeloid cells or the so called Myeloid-derived suppressor cells (MDSCs) are found to be present in higher numbers in cancer patients' PBMCs and in tumor infiltrating cells. All-trans retinoic acid (ATRA) is a natural vitamin A metabolite that's capable of inducing MDSC maturation and differentiation at uM concentrations. HF1K16 is an ATRA liposome formulation developed by Hangzhou Highfield Biopharm that aims to deliver ATRA to the tumor microenvironment by i.v. infusion for MDSC mediated immuno-therapeutic effects. Methods: The HF1K16 phase Ia clinical trial (NCT05388487) is being conducted to study the tolerability and safety of HF1K16 in patients with refractory solid tumors based on a "3+3" dose escalation scheme. HF1K16 infusions were given every other day for 2 weeks followed by a break week, and the 3wk cycle were repeated until EOT. Safety and tolerability records, repeated dose PK parameters, as well as exploratory PD analysis of PBMC samples are evaluated during the first cycle of treatment. Efficacy evaluations are followed every 6 weeks or less until EOT. Results: As of January 30, 2023, there have been 11 patients enrolled into the study in the dose groups of 45 mg/m2, 90mg/m2 and 120 mg/m2. The patient diagnosis and up to date treatment information is shown. Clinical trial information: NCT05388487 . Conclusions: HF1K16 is well tolerated at the 45 mg/m2 and 90 mg/m2 dose levels when given as monotherapy. Using the RECIST 1.1 criteria, one patient achieved an objective response with a progressive reduction of the target lesion from 70mm to 23.7mm. Four patients had PFS longer than 3 months. There is a subgroup of five enrolled patients who have recurrent and refractory Glioblastoma with multiple prior treatments. Three of them had control of disease and are still under treatment. The study is also still on going. We will collect more data based on additional enrolled cases and plan for the next phase study of HF1K16. [Table: see text]
Development of a microbead based immunoassay to detect circulating soluble HLA-E: Application in cancer immunobiology.
Authors: Varun Kanangat, Claire Auger, Imad Tarhoni, Megan K. Marshalla, David Gerard, Ahmed Abdelkader, Jeffrey Allen Borgia
Journal: Journal of Clinical Oncology (2023)

e17606 Background: The Human Leukocyte Antigens [HLA] gene complex is subdivided into classical (HLA-A, B, and C) and non-classical (HLA-E, F, G, and H) loci. These genes are associated with immune modulation and immunopathogenesis in cancer, though the roles of non-classical HLA molecules are poorly understood. Here, we explored potential expression patterns of soluble HLA-E (sHLA-E) in patient sera across a range of common malignancies to identify potential disease applications for future study. Methods: Quantitative Luminex immunobead assay were developed for sHLA-E using methods we previously defined. In the first phase of this study, we assessed sHLA-E protein levels across a range of treatment-naïve metastatic malignancies (n=5 each), including breast, lung adenocarcinoma, lung squamous cell carcinoma, colorectal, head and neck, ovarian, melanoma, and sarcoma. Based on these results, we refocused our efforts on a second cohort surgically treated by gynecologic oncology for either non-malignant (n=13) or malignant (n=42) lesions of ovarian origins. One-way ANOVA or Independent sample t tests, with normality confirmed via Levene's Test for Equality of Variances, were used to identify statistical relationships. Results: There were significantly (p&lt;0.05) higher levels of sHLA-E protein in ovarian cancer relative to other cancer types surveyed. In the second phase of the study, serum specimens from patients undergoing surgery for a suspected gynecological malignancy were tested for sHLA-E. This study also showed the significantly high expression of sHLA-E in ovarian cancer relative to those with nonmalignant lesions of ovarian origins (p=0.035) that was independent of FIGO grade (p&gt;0.05). For comparison, levels of sHLA-E were not significantly elevated for tumors of endometrium/ endomyometrium origins (n=76; p=0.270) relative to baseline of benign cases. Conclusions: We identified a highly specific statistical relationship for a circulating isoform of HLA-E in ovarian cancer in our cohorts. The significance of these findings in relation to clinical outcomes or treatment response will be explored in future studies. [Table: see text]
A pilot study of lymphodepletion intensity for PBMC-derived, neoantigen-specific CD8+ T cells (Neo-Ts) therapy in patients with advanced solid tumors.
Authors: Dandan Li, Chao Chen, Jingjing Li, Jianhui Yue, Ya Ding, Hailun Wang, Zhaoduan Liang, Le Zhang, Si Qiu, Geng Liu, Yan Gao, Ying Huang, Dongli Li, Wei Liu, Xizhi Wen, Bo Li, Xiaoshi Zhang, Xi Zhang, Rui-Hua Xu
Journal: Journal of Clinical Oncology (2023)

2545 Background: Adoptive T cell therapy (ACT) using neoantigen-specific CD8+ T cells (Neo-Ts) derived from patient PBMC was recently developed aiming to target individual patient’s unique tumor mutations and increase treatment efficacy. But the optimal lymphodepletion intensity for Neo-T therapy has yet to be determined. Methods: In this phase I clinical trial (NCT02959905), we generated Neo-Ts from patients with locally advanced or metastatic melanoma or colon cancers that were refractory to standard therapies, and evaluated the effects of lymphodepletion at various dosages (high: 2x500 mg/m 2 cyclophosphamide and 2x25 mg/ m 2 fludarabine; low: 1x500 mg/m 2 cyclophosphamide and 2x25 mg/ m 2 fludarabine; and no lymphodepletion) during Neo-T therapy. The primary end point was safety and the secondary end point was objective response rate (ORR). Results: We showed that Neo-T therapy was safe with lymphodepletion at dosages from no lymphodepletion to high intensity. The median PFS was 7.1 months (95% CI:3.7-9.8), and median overall survival (OS) was 16.8 months (95% CI: 11.9-31.7). The ORR was 33.3% (3/9) among all groups. Three patients achieved PR, two of them were in the group without lymphodepletion. One of the PR patients refractory to prior anti-PD-1 therapy also responded to Neo-T therapy. Neoantigen specific TCRs were examined in two responding patients and showed expansion and persistence after treatment. Conclusions: Neo-T therapy with low intensity lymphodepletion or no lymphodepletion could be a safe and promising regimen for advanced solid tumors. Clinical trial information: NCT02959905 .
A prospective study of FOLFIRI plus aflibercept as second-line treatment after failure of FOLFOXIRI plus bevacizumab in patients with unresectable/metastatic colorectal cancer (CRC): EFFORT study.
Authors: Hironaga Satake, Koji Ando, Hisateru Yasui, Yuji Negoro, Tatsuya Kinjo, Koutarou Yuge, Kenji Baba, Hiroyuki Orita, Keiji Hirata, Mototsugu Shimokawa, Akitaka Makiyama, Hiroshi Saeki, Eiji Oki, Hideo Baba
Journal: Journal of Clinical Oncology (2023)

3549 Background: FOLFOXIRI plus bevacizumab (BEV) is a first-line treatment option for patients with unresectable or metastatic CRC. However, there are no clear recommendations for second-line therapy after failure of FOLFOXIRI plus BEV. The EFFORT study investigated whether FOLFIRI plus aflibercept is active following FOLFOXIRI plus BEV in unresectable/metastatic CRC. Methods: EFFORT was an open-label, multicenter, single arm phase II study. Patients with unresectable/metastatic CRC who failed FOLFOXIRI plus BEV as a first-line therapy received aflibercept plus FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m 2 IV over 90 min, with levofolinate 200 mg/m 2 IV over 2 hours, followed by fluorouracil 400 mg/m 2 bolus and fluorouracil 2400 mg/m 2 continuous infusion over 46 hours) every 2 weeks on day 1 of each cycle. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). To achieve 80% power to show a significant benefit with a one-sided alpha level of 0.10, assuming a threshold PFS of 3 months and an expected value of at least 5.4 months, 32 patients needed to be enrolled. Major secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Results: From April 2019 to May 2021, 35 patients were enrolled and FAS included 34 patients (one patient who did not met eligibility criteria was excluded). Of them, 18 were males, median age was 63 years (range: 32-78) and ECOG Performance Status was either 0 (n = 28) or 1 (n = 6). The primary tumor was left-sided in most patients (23/34) and 27 patients had liver metastases. And 23 patients had RAS mutation. The primary endpoint was met with a median PFS of 4.3 months [80% CI: 3.7-5.1]. The median OS was 15.2 months [95% CI: 8.9-22.7]. Objective tumor responses were CR (n = 1), PR (n = 4), SD (n = 21) or PD (n = 8). ORR was 14.7% (5/34) [95% CI: 5.0-31.1], and disease control rate was 76.5% (26/34) [95% CI: 58.8–89.3]. Main grade 3 or 4 adverse events were neutropenia (7/35, 20.0%), thrombopenia (3/35, 8.6%), leucopenia (2/35, 5.7%), and hypertension (3/35, 8.6%). No severe proteinuria and no treatment-related death were reported. Conclusions: Aflibercept plus FOLFIRI given after failure of FOLFOXIRI plus BEV is active and shows a manageable safety profile. This regimen maybe a useful as second-line treatment option in such patients. Clinical trial information: jRCTs071190003 .
Efficacy of a hematology/oncology podcast curriculum at a community-based internal medicine program.
Authors: Madeline Campbell Fitzpatrick, Jacob Carter, Ronak Mistry, Daniel Hausrath, Vivek Patel
Journal: Journal of Clinical Oncology (2023)

11036 Background: Medical podcasts have gained increasing popularity; however, there is limited evidence regarding their utility as an effective learning resource in Graduate Medical Education. Community-based internal medicine (IM) residents often have less exposure and education in hematology and oncology. To address this barrier, we developed a novel trainee-level hematology/oncology podcast curriculum to improve foundational knowledge for IM residents. Methods: A hematology/oncology podcast curriculum was implemented for IM residents at a community-based residency program in the 2022-2023 academic year. We developed ten episodes regarding workup and management of cytopenias, oncologic emergencies, and hematologic emergencies. We distributed anonymous pre- and post-intervention surveys to understand the impact of the podcast curriculum on a 5-point Likert scale on residents’ self-perception of their knowledge. Two sample paired t-test was used to compare mean differences in surveys. Results: A total of 17/27 residents (63%) completed the pre-intervention survey, and 9/27 residents (33%) completed the post survey. The pre-survey was more heavily weighted towards residents earlier in their training with 53% PGY1s, 29% PGY2s, and 18% PGY3s. With 5 being entirely comfortable, there was a statistically significant increase in mean comfort level in the workup and management of various cytopenias (2.65 to 4.0, p &lt; 0.01) and the management of oncologic emergencies (2.29 to 4.2, p &lt; 0.01). Comfort level in the management of hematologic emergencies numerically improved from 3.35 to 3.57 but was not statistically significant. Most residents (90%) agreed or strongly agreed that the fundamentals of hematology/oncology were amenable to a podcast platform. Many residents found this modality convenient and performed other activities while listening to the podcast including driving (82%) and exercising (55%). The majority of residents who completed the post-survey (64%) reported that they will continue to use podcasts to supplement their medical education. Conclusions: Community based IM residents’ comfort with the field of hematology/oncology improved following the medical podcast educational intervention. Residents found the learning platform amenable to the fundamentals of hematology/oncology and will continue to utilize medical podcasts to supplement their education. Our successfully piloted podcast curriculum can be adapted to other IM programs to improve foundational knowledge in hematology/oncology.
In vivo anti-tumor effects of XON7 in association with ICIs.
Authors: Carine Ciron, Odile Duvaux, Françoise Shneiker
Journal: Journal of Clinical Oncology (2023)

e14520 Background: The advent of immune checkpoint inhibitors (ICIs) has rapidly transformed the treatment paradigm for multiple cancer types. This remarkable shift has been driven in large part by unprecedented durability that is characteristic of ICIs responsiveness. However, ICIs promote tumor cell immune escape; indeed, the response rate to single agent PD-1 blockade in unselected patients ranges from 40 to 70% in some diseases, while the response rates in most other approved diseases is limited to 10–25%. These observations support the need to strengthen immunotherapy and bring additional benefits for patients. XON7, is a glyco-humanized polyclonal antibody (GH-pAb) targeting multiple tumor antigens and active in vitro and in vivo in several solid tumors and hematological malignancies. Methods: A human lung carcinoma chorio-allantoic membrane (CAM) model was used to evaluate the efficacy of XON7 + anti PD-1 treatment. Fertilized white Leghorn eggs were incubated until Day 9, then inoculated in the upper CAM with 1.10 6 H460 cells. Treatments were administrated at E10, E12, E14, E15 and E17. Two groups were included: control group (n=20) received a non-immune GH-pAb + anti-PD-1 (10 mg/kg + 2,5 mg/kg respectively); treated group (n=20) received XON7 and anti-PD-1 at the same doses. Upper CAM, lower CAM and brain were collected from the embryos at E18. Tumor growth was evaluated by tumor weight using one-way ANOVA. Metastasis were quantified by qPCR for Alu sequences. Immune cell infiltration was analyzed by RT-qPCR with specific primers for chicken CD3, CD4 and CD8 sequences, with GAPDH as reference gene expression. Results: Significant reduction in tumor growth (~30%, p=0.02) and metastasis (&gt;90%, p=0.001) was observed in both the brain and the lower CAM in the XON7+ICI group compared to control group. No differences in lymphocyte infiltrates (CD3, CD4, and CD8) were observed between groups. However, a significant increase in the M1/M2 ratio was observed in the XON7 + anti-PD-1 group over control. No toxicity from the treatment appeared in this model. Conclusions: In vivo data showed a significant increase of response rate and decrease of metastasis when XON7 is associated with anti PD-1. Combination of GH-pAb with ICI could constitute an immunotherapy combination likely to overcome resistance to anti-PD1.
Find: Immunomodulation after a fasting mimicking diet analyzed by Nanostring and multispectral flowcytometry in healthy volunteers: A pilot study.
Authors: Nadia de Gruil, Marij JP Welters, Sam Kaart, Hanno Pijl, Sjoerd H. van der Burg, Judith R. Kroep
Journal: Journal of Clinical Oncology (2023)

e14560 Background: An increasing number of clinical trials, including our randomized phase III trial (NCT05503108), are investigating the potential benefit of short-term fasting using a fasting mimicking diet (FMD) on the anti-tumor effect of chemotherapy. Preclinical research suggests that FMD promotes infiltration of CD8+ T-cells, while decreasing regulatory T-cells (Treg). Extensive immunoprofiling is needed to investigate the immunomodulatory effects of FMD alone and guide ongoing translational trials on FMD as an adjunct to chemotherapy in patients with cancer. Methods: FIND is a prospective pilot study, which included 9 healthy volunteers who followed a 4-day FMD every 3 weeks, 2 times (NCT04833439). Peripheral blood samples were collected in a fed state (baseline), after overnight fasting (overnight) and directly after the second cycle of FMD (final). Metabolic markers (IGF1, glucose, ketone bodies) to ensure ketosis were measured in the plasma. The RNA from white blood cells was isolated and transcriptomics was performed with the Nanostring IO360 human Pancancer panel, and analyzed by nSolver Advanced analysis, Graphpad Prism and String analysis. Statistical testing was done using Wilcoxon signed-rank tests in R-studio. In addition, 40-plex spectral AURORA flow cytometry for immune cell composition with FlowJo analysis was performed. This study was approved by the local Medical ethical committee (NL76033.058.21). Results: Paired analysis of the Nanostring data identified 56 differentially expressed genes (DEG) comparing baseline and final samples initially, of which 19 genes showed at least 1.2 log 2 fold-change in at least half of the participants. String analysis indicated that the DEGs were associated with fatty-acid metabolism, T-cell and myeloid cell function and immune regulatory pathways. Cell typing showed an increase in cytotoxic NK CD56dim cells (p=0.031) and a decrease in Tregs decreased (p=0.063) after FMD. In-depth analysis of gene specific pathway enrichment and immune cell profiling by flow cytometry will be presented. Conclusions: The expression profile of 56 genes in circulating immune cells changed after 2 FMD cycles, next to fatty-acid metabolism affecting the composition and function of both T-cells and myeloid cells and their regulation. Altogether, FMD induced immunological changes that could support cancer treatment and guide immunomonitoring in future trials evaluating the effects of FMD in cancer treatment. Clinical trial information: NCT04833439 .
Pan-cancer analysis to identify molecules interacting with CasL-Like 2 to promote angiogenesis via mTOR/HIF1A/VEGFA pathway in hypoxia tumor environment.
Authors: Yu-xin Song, Lei Li, Jian-yun Lan, Jinhai Tang
Journal: Journal of Clinical Oncology (2023)

e15002 Background: Cytoskeleton dynamics generate power for diverse motile and morphogenetic processes in eukaryotic cells. Aberrant actin dynamics are closely associated with pathological conditions and implicated in the occurrence of various tumors. The underlying mechanisms remain to be explored. This study aims to identify a unique redox enzyme, Molecules Interacting with CasL-Like 2 (MICALL2), as a regulator of actin filaments during tumorigenesis and to evaluate its potential value in predicting drug sensitivity to anti-angiogenesis agents. Methods: First, bioinformatic analysis was used to demonstrate MICALL2 expression level across distinct cancers and its relationship with clinical characteristics from TCGA and CPTAC databases. Functional enrichment analysis and whole-mountin situ hybridization were performed. Gene correlation analysis and IHC were used to detect the correlation between MICALL2 and HIF family. Next, chosen kidney renal clear cell carcinoma (KIRC) as a research object, the location of MICALL2 and actin was determined by immunofluorescence. IHC on MICALL2, HIF1A, VEGFA, CD31, CD34 of 44 clinical KIRC tissue samples was performed. The role of MICALL2 in proliferation, hypoxia and angiogenesis of KIRC cells was investigated using EDU staining, CCK-8 assay, ROS analysis, flow cytometry, and tubule formation assays. The effect of MICALL2 on the mTOR-related signal pathway was evaluated by western blot. Last, drug sensitivity analysis was obtained from the GDSC, CTRP, and PRISM databases to reveal the relationship between MICALL2 and anti-angiogenesis agents and cytoskeleton-regulating drugs. Results: MICALL2 expression was elevated in most cancers and correlated with poor survival outcomes. Pan-cancer analysis demonstrated that MICALL2 was co-expressed with HIF family members and strongly linked to angiogenesis pathway. Interfering the translation of MICALL2 during zebrafish embryogenesis resulted in defective caudal vein plexus morphogenesis. Additionally, KIRC patients with high MICALL2 expression displayed enhanced HIF1A expression and increased CD34-labeled neovascularization. In KIRC cells, MICALL2 was found co-located with F-actin. MICALL2 overexpressed KIRC cells exhibited more aggressive behaviors, with the tumor microenvironment remodeling to a more hypoxia condition. Up-regulation of MICALL2 promoted tumor angiogenesis via activating a novel mTOR/HIF1A/VEGFA pathway. Furthermore, tumor patients with high MICALL2 expression were more likely to be resistant to anti-angiogenesis agents and microtubule depolymerization inhibitors, but sensitive to actin polymerization inhibitors. Conclusions: Our results suggest that MICALL2 plays a crucial role in tumor angiogenesis and may be a potential predictor of anti-angiogenic agent sensitivity across multiple cancers.